Method of preparing phenylacetic acid

ABSTRACT

A method of preparing phenylacetic acid comprising phase-transfer carboxylation of benzyl sodium in the presence of a salt catalyst.

CROSS-REFERENCE TO RELATED APPLICATION

The present application is a continuation-in-part of copending andcoassigned application Serial No. 11/177,893, filed Jul. 8, 2005 byShabanov and Ramazanova.

FIELD OF INVENTION

The present invention relates to methods of preparing phenylacetic acid.

BACKGROUND OF INVENTION

Current processes for the production of phenylacetic acid usingsodium-toluene, and chlorobenzene as precursors are slow and do notprovide a high yield. Non-catalytic methods are not cost-effective,stable methods for the production of phenylacetic acid because of thelong duration of the benzylchloride metaliation, benzylsodiumproduction, and carboxylation stages. This makes the current processesexpensive and time-consuming and therefore unsuited forcontinuous-process industrial production of phenylacetic acid.

Further, current processes for the production of phenylacetic acid canbe used only under laboratory conditions aiming at producing smallamounts of the product. Further, the purity of the product obtained isnot high due to the formation of byproducts (phenylmalonic acid, etc.),which requires supplementary purification. This creation of byproductsreduces output to 65-70%. Further, current processes are environmentallyunfriendly and are not capable of being carried out in a stainless steelreactor. Thus, the current processes for the production of phenylaceticacid are not economically expedient and fail to be useful as continuousmethods of phenylacetic-acid industrial production.

A need exists, therefore, for a process that reduces the process timeand increases the yield of phenylacetic acid, thereby providing acommercially-viable method for the production of phenylacetic acid.

All references cited herein are incorporated by reference to the maximumextent allowable by law. To the extent a reference may not be fullyincorporated herein, it is incorporated by reference for backgroundpurposes and indicative of the knowledge of one of ordinary skill in theart.

SUMMARY OF INVENTION

The principles of the present invention are embodied in methods ofpreparing phenylacetic acid utilizing phase-transfer carboxylation ofbenzyl sodium in the presence of a salt catalyst.

Embodiments of the present principles realize a number of significantadvantages. Among other things, application of these principlesadvantageously reduces process time and the formation of byproducts, andincreases the phenylacetic acid yield.

BRIEF DESCRIPTION OF DRAWINGS

For a more complete understanding of the present invention, and theadvantages thereof, reference is now made to the following descriptionstaken in conjunction with the accompanying drawings, in which:

FIG. 1 is a block diagram of a representative system embodying theprinciples of the present invention;

FIG. 2 is a schematic flow diagram illustrating an exemplary processembodying the principles of the present invention; and

FIG. 3 is a schematic flow diagram illustrating another exemplaryprocess embodying the principles of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The principles of the present invention and their advantages are bestunderstood by referring to the illustrated embodiment depicted in FIGS.1-2 of the drawings, in which like numbers designate like parts.

Referring to FIG. 1, there are four basic steps to the inventivephenylacetic acid production process. Some of the basics of the processcan be found in Gilman, Henry, et al, “Benzylalkali Compounds,” J. Am.Chem. Soc., Vol. 62,1514 (1940); Nobis, John, et al, “Phenylsodium Routeto Phenylacetic Acid and Dimenthyl Phenylmalonate,” Indus. Eng. Chem.Vol. 46, No. 3, 539 (1954); Morton, Avery and Ingenuin Hechenbleikner“Condensations by Sodium. VII. Solvent Exchange Reactions, Preparationof Phenylmalonic Acid, and Comments on Some Mechanisms of Reactionswhich Employ Sodium,” J. Am. Chem. Soc., Vol. 58, 2599 (1936); Morton,Avery, et al, “Condensations by Sodium. XII. Mechanism of Formation ofPhenylmalonic Acid and the Syntheses of Butyl- and Phenylmalonic Acidsfrom Monocarboxylic Acids,” J. Am. Chem. Soc., Vol. 60,1426 (1938); R.L. Letsinger, “The Preparation of Optically Active Hydrocarbons by theWurtz Reaction,” J. Am Chem. Soc., Vol. 70, 406 (1948); Gilman, Henry,and H. A. Pacevitz, “The Carbonation of Organoalkali Compounds,” J. Am.Chem. Soc., Vol. 62,1301 (1940); Hansley, V. L., “Sodium Reduction ofFatty Acid Esters,” Indus. Eng. Chem., Vol. 39, 55 (1947); and Pacevitz,H. A., “Lateral Organoalkali Compounds,” Chem. Abstracts, Vol. 36, 4475(1942); incorporated herein by reference.

First, an alkali metal, a phenyl halide, a solvent, and a catalyst arecombined. An example of this is combining sodium, chlorobenzene,toluene, and a catalyst. Under proper processing conditions, describedherein, the sodium and chlorobenzene react to form phenylsodium. Second,this reaction mixture is boiled, which causes the phenylsodium andtoluene to react and form benzylsodium. Third, the reaction mixture iscarbonized, preferably over dry ice, hydrolyzed, and acidified, whichleads to the formation of phenylacetic acid. Finally, the phenylaceticacid is crystallized and recovered from the reaction mixture.

In more detail, referring to FIG. 2, metallic sodium and toluene areadded to a preliminary reactor 1 for sodium disintegration. Aspecial-purpose, high-speed mixer 12, preferably capable of achieving atleast 10,000 revolutions per minute, is switched on to crush the sodiumand to produce a sodium-in-toluene suspension. Preferably, the mixerneed only be used for around 1-1.5 minutes. The suspension is thencooled down to around 25-30° C.

A solution containing equivalent amounts of chlorobenzene and drytoluene with around 0.0005-0.001% catalyst calculated on sodium arecontained in a chlorobenzene tank 11. Effective catalysts are cryptandsand crown compounds, such as crown ethers. Preferably, themacrocyclic-catalyst will have a cavity size which corresponds to theion radius of sodium. The preferred catalysts are cryptand [2,2,2] and16-crown-5. An equivalent amount of the solution from the chlorobenzenetank 11 is added to and mixed with the preliminarily prepared suspensionof metallic sodium in toluene in the preliminary reactor 1. This mixtureis transferred to a phenylsodium-conversion reactor 3 with the sodiumparticle size not to exceed 20-25 microns.

Alternatively, the solution from the chlorobenzene tank 11 can be addeddirectly to the phenylsodium-conversion reactor 3 without premixing thesolution with the suspension in the preliminary reactor 1. Anotheralternative is to add the chlorobenzene and catalyst to the preliminaryreaction mixture in the preliminary reactor 11 prior to initial mixing.

For a phenylsodium-conversion reactor of 2 liter volume, the feed rateof the reagents to the phenylsodium-conversion reactor should be around4.3 mol/hr. The reactor can have an external cooling jacket.

The temperature in the phenylsodium-conversion reactor 3 is maintainedin the range of around 27-40° C. by regulating the reagent feed ratesand the external cooling of the phenylsodium-conversion reactor 3. Thepreferred amount of catalyst is 0.001% based on sodium. More than 0.001%catalyst can be used, but the economics for larger amounts of catalystare not as good as for the preferred amount. All process steps should becarried out in an inert atmosphere such as nitrogen. Generally, any drygas may be used in this process.

Approximately every 10 minutes the suspension accumulated in thephenylsodium-conversion reactor 3 is transferred into a reserve tank 6where mixing is continued. The temperature of the reserve tank 6 ismaintained preferably at 30-40° C. Upon reaching a desired volume, thesuspension in the reserve tank 6 is transferred to abenzylsodium-conversion reactor 7. The suspension is boiled in thebenzylsodium-conversion reactor 7. Boiling is maintained forapproximately 0.5-1.5 hours, preferably for 1.0-1.5 hours.

After boiling in the benzylsodium-conversion reactor 7, the preparedbenzylsodium suspension is transferred to a cooling tank 9 where thebenzylsodium suspension is cooled to 25° C. Following cooling in thecooling tank 9, the benzylsodium suspension is discharged by jet ontodisintegrated dry ice in the carbonation reactor 10 and slowly mixed.Alternatively, liquid CO₂ may be used. The dry ice in the carbonationreactor 10 is in an amount of 20 fold mole excess based on benzylsodium.

After volatilization of the CO₂, the residue is hydrolyzed with water bymixing and cooling in the carbonation reactor 10. The volume of waterused for hydrolysis is equal to 25-35% of the toluene volume.

The aqueous layer is then separated from the toluene layer and isacidified, preferably with hydrochloric acid. The pH is preferablylowered to a pH of approximately pH 2.

The phenylacetic acid is then crystallized and separated from the water.The phenylacetic acid prepared by the invented process has a meltingtemperature of 75-76° C.

1. Experiment:

4.7 g. of sodium, 30 ml of absolute toluene and 6 mg of catalyst are putinto a stainless-steel preliminary reactor that has a mixer capable ofmixing at 10,000 revolutions per minute, a heater, a backflow condenser,a viewing window, and a cooling jacket. All processes are carried out ina dry-nitrogen atmosphere. The reactor is heated up to the tolueneboiling point. Then the high-speed mixer is switched on for 1-1.5minutes for sodium crushing.

The suspension is then cooled down to 25-30° C. and placed in aphenylsodium-conversion reactor. 5-8ml of a chlorobenzene and toluenesolution, made by mixing the 2 reagents in equal proportion withcatalyst, is added to toluene-sodium suspension while mixing and coolingthe reactor to 27-40° C. The reaction begins immediately and blacksediments of phenylsodium are generated in the reactor. The temperatureof reaction mixture is kept at 27-40° C. The chlorobenzene metallizingreaction takes approximately 1 hour.

The suspension of phenylsodium is taken from the phenylsodium-conversionreactor to a reserve tank, where reaction is completed in a nitrogenatmosphere. In order to transform phenylsodium into benzylsodium, thecontents of the reserve tank are placed into a benzylsodium-conversionreactor, where the suspension boils for 1-1.5 hours. While boiling, thesolution's color gets brick-red and then black again.

Upon completion of the reaction, the hot solution is removed from thebenzylsodium-conversion reactor and placed into a cooling tank. Then assoon as possible, the cooled reaction mass is poured into crushed dryice in a carbonation reactor and mixed. When vaporization of the CO₂ iscompleted, 20 ml of water is added to the residue during cooling andmixing. The water layer is then separated and acidulated withhydrochloric acid to a pH around pH 2. The generated sedimentphenylacetic acid is separated by filtration in a vacuum-filter. 12.5 g.of phenylacetic acid (92%) with melting point 77° C. is produced. Theresults of other experiments are given in the Table 1. TABLE 1Experimental results of PhAA production in the absence and presence ofcatalyst respectively PhAA production PhAA yields in the absence in thepresence of catalyst, % of catalyst, % Rate of addition of Rate ofaddition toluene solution of of toluene solution Time of chlorobenzeneand of chlorobenzene and boiling of toluene suspension of toluenesuspension phenylsodium sodium, 4.3 mole/hr. of sodium, 4.3 mole/hr. intoluene, hr. 2.5 3.5 4.3 5 2.5 3.5 4.3 5 0.5 16.2 18.9 27 33 66 74 75 701 34.6 40.5 48 54 83.5 90 94.5 89 2 42.8 44.8 52 58 83.4 89.8 93.7 86.73 52.5 60.4 62.5 69 80.8 90.6 90.3 85.9 4 49.6 58.4 66.5 — 76 87 88 80.8

Table 1 shows that including a catalyst greatly increasesphenylacetic-acid yield . The highest yield of the product is observedwhen the time of boiling in toluene equals 1 hour time. Further increasein boiling time causes a decrease in desired product field. Also, theapplication of a catalyst improves the stability of the results.

It was also observed that the increase in catalyst amount to 0.001%leads to a raise in yield of the desired product. Further increases incatalyst amount do not generally give an increase of the desiredproduct.

The principles of the present invention are also embodied in methods forforming phenylacetic acid using phase transfer techniques, particularlyto the phase-transfer catalytic carboxylation of benzyl-sodium intoluene/benzene in presence of a salt such as [N(C₄H₉)₄]X.

Carboxylation of benzyl-sodium in solid-liquid phase-transfer catalysiscondition realizes many advantages. For example, carboxylation processesusing the phase-transfer catalysis techniques of the present inventiveprinciples consume less dry ice. Further, these phase-transfer catalysistechniques prevent minor byproduct formation reactions. Additionally,phase-transfer catalysis techniques also the simplify phenylacetic acidpreparation process.

According to the principles of the present invention, a carboxylationreaction 1, 2 and 3 is carried out by mixing a toluene/benzenesuspension of benzyl-sodium with a toluene solution of thetetra-ethyl-ammonium-chloride and adding the prepared mixture to crusheddry ice.

One representative carboxylation of benzyl sodium process according tothe inventive principles is shown in the process diagram of FIG. 3. To11.45 g (0.1 mol) of toluene/benzene solution of benzyl-sodium, preparedfrom 11.25 g (0.1 mol) of chlorobenzene, 9.4 g (0.2 mol) of sodium and60 ml of toluene as described above and shown at Block 31 in FIG. 3, isadded 1.1 g of [(C₄H₉)₄N]X(X═Cl, Br) in toluene (12 ml) under nitrogenat 25-27° C. (Block 32). The mixture is stirred 15 min and is addedslowly to crushed dry ice (Block 33). The mixture is kept until removalof dry the ice (in CO₂ form), and then the residue is treated with HCl(hydrochloric) acid (10%, pH=1) (Block 34) and the sediment ofphenylacetic acid is separated and crystallized from water (Block 35).Yield of pure phenylacetic acid is 13.32 g (98%). Melting point ofprepared product is 77° C.

The toluene/benzene solution containing the phase-transfer catalyst maybe recycled many times in the carboxylation process with no loss incatalytic activity. Phenylacetic acid is thus obtained to the extent ofmore than 800 moles per mole of [(C₄H₉)₄N]Br taken.

Another important advantage of this system is the possibility ofachieving selective carboxylation of benzyl-sodium yield of phenylaceticacid, and a carboxylation yield to 96-98%. An important practical aspectof this process is the continuous separation of the product from thecatalyst, which in effect heterogenizes the homogenous catalyst. Thispoint accounts for the high catalyst turnover, the selectivityencountered in the carboxylation of benzyl-sodium and the high activityof the catalyst.

Table 2 summarizes experimental results demonstrating carboxylationprocesses using the phase-transfer catalysis techniques of the presentinventive principles. TABLE 2 Mass-balance of laboratory pilot plantexperiment on preparation of phenylacetic acid Amount of Amount Compoundformed and Compounds of taken prepared and returned taken to to reactionreturned other compounds, No reaction compounds, g No reaction, g g 1Chlorobenzene 56.3 1 Phenylacetic 66.7 acid 2 Sodium 27.0 2 Returned123.62 toluene 3 Toluene 187.5 3 Formed 35.9 benzene 4 Dry ice 440 4Lost toluene 14.58 5 Hydrogen 214 5 Lost benzene 3.1 chloride acid 10% 6Catalyst 0.27 6 Returned dry 418 ice in from of CO₂ 7 7 Catalyst 0.27 88 Water 192.6 9 9 Minor products 2.3 10 10 NaCl 68 Sum 925.07 Sum 925.07* Theoretical yield of phenylacetic acid on chlorobenzene is 98%

Although the invention has been described with reference to specificembodiments, these descriptions are not meant to be construed in alimiting sense. Various modifications of the disclosed embodiments, aswell as alternative embodiments of the invention, will become apparentto persons skilled in the art upon reference to the description of theinvention. It should be appreciated by those skilled in the art that theconception and the specific embodiment disclosed might be readilyutilized as a basis for modifying or designing other structures forcarrying out the same purposes of the present invention. It should alsobe realized by those skilled in the art that such equivalentconstructions do not depart from the spirit and scope of the inventionas set forth in the appended claims.

It is therefore contemplated that the claims will cover any suchmodifications or embodiments that fall within the true scope of theinvention.

1. A method of preparing phenylacetic acid comprising phase-transfercarboxylation of benzyl sodium in the presence of a salt catalyst. 2.The method of method of claim 1, comprising: combining chlorobenzene andsodium in a solution to produce a mixture; adding the catalyst; addingdry ice to the mixture; maintaining the mixture until removal of the dryice in gaseous form; treating the remaining residue with hydrochloricacid; and separating the phenylacetic acid from the remaining solutionincluding the catalyst.
 3. The method of claim 1, wherein the catalystcomprises a tetra-ethyl-ammonium-halide.
 4. The method of claim 3,wherein the catalyst is selected from the group consisting oftetra-ethyl-ammonium-chloride and tetra-ethyl-ammonium-bromide.
 5. Themethod of claim 2, wherein combining chlorobenzene and sodium in asolution comprises combining chlorobenzene and sodium in a solution oftoluene/benzene.
 6. The method of claim 2, wherein separating thephenylacetic acid from the solution including the catalyst comprisescontinuous separation of the phenylacetic acid and the catalyst.
 7. Themethod of claim 2, further comprising recovering the catalyst insolution for reuse.
 8. The method of claim 2, further comprisingcrystallizing the phenylacetic acid from water.
 9. A method of preparingphenylacetic acid comprising: combining benzyl-sodium with atetra-ethyl-ammonium-halide catalyst; adding dry ice to the mixture;maintaining the mixture until removal of the dry ice in gaseous form;treating a residue with hydrochloric acid; and separating thephenylacetic acid from the remaining solution including the catalyst.10. The method of claim 9, wherein the a tetra-ethyl-ammonium-halidecatalyst is selected from the group consisting of atetra-ethyl-ammonium-chloride and a tetra-ethyl-ammonium-bromide. 11.The method of claim 9, further comprising: recovering the catalyst inthe remaining solution; and reusing the recovered catalyst during asubsequent combination of chlorobenzene and sodium for preparation ofphenylacetic acid.
 12. The method of claim 9, wherein adding dry ice tothe mixture comprises adding crushed dry ice to the mixture.
 13. Themethod of claim 9, further comprising combining chlorobenzene withsodium in a toluene solution to produce the benzyl-sodium.
 14. Themethod of claim 9, wherein combining benzyl-sodium with atetra-ethyl-ammonium-halide catalyst comprises adding the atetra-ethyl-ammonium-halide catalyst with the benzyl-sodium in tolueneunder nitrogen at a temperature of in the range of approximately 25 to27 degrees Celsius.
 15. The method of claim 9, further comprisingstirring the mixture while slowly adding the dry ice.